The invention relates to active substance plasters consisting of a backing material and an at least partially applied adhesive composition, the plaster comprising the active substance or, if desired, two or more active substances which are delivered to the skin, and to processes for producing the plasters.
Strongly adhering plasters are usually coated over their entire area with a zinc-rubber adhesive composition. The sticking of such products to the skin gives rise, following their removal, to marked skin irritation and to mechanical stressing of the skin. Without auxiliary means, it is impossible to break the bond painlessly.
In some cases, there are allergic reactions. Furthermore, the adhesive compositions used often lead to a transfer of composition onto the skin.
The use of skin-friendly adhesive compositions, such as acrylate adhesive compositions and hydrogels, is out of the question because of their low shear stability and tack. Improvement through aftertreatment, especially crosslinking, is possible, although the result remains unsatisfactory as a whole. The proprioreceptive effect is less than that of systems with a resin-rubber adhesive composition.
Other known adhesive systems based on conventional block copolymers are, on the one hand, not skin-friendly, owing to the high level of added stabiliser, or because of their high cohesiveness have been found suitable to date only for industrial applications, or, on the other hand, they cannot be formulated for strong adhesion and sticking to the skin.
The abovementioned adhesive compositions are pressure-sensitive self-adhesive compositions, it being possible for the compositions present in a carrier matrix for processing. The term carrier matrix is understood to refer to common organic or inorganic solvents or dispersion media.
Systems without a carrier matrix are referred to as 100% systems and are likewise not unknown. They are processed in the elastic or thermoplastic state. A common mode of processing is that of the melt. Pressure-sensitive hotmelt adhesive compositions of this kind have also already been described in the prior art. They are based on natural or synthetic rubbers and/or other synthetic polymers.
An advantage of the 100% systems is that they avoid the operation of removing the carrier matrix, i.e. the auxiliary means, thereby raising the productivity of processing and at the same time reducing the expenditure on machinery and the energy costs. In addition, this reduces the occurrence of residues of the carrier matrix, which, in turn, promotes a reduction in the allergenic potential.
Because of their high level of hardness, sticking to the skin is a problem for such 100% systems.
It is also known to apply such self-adhesive compositions not only over the entire area but also in the form of a pattern of dots, for example by screen printing (DE-C 42 37 252), in which case the dots of adhesive can also differ in their size and/or distribution (EP 0 353 972 B), or by intaglio printing of lines which interconnect in the longitudinal and transverse direction (DE-C 43 08 649).
The advantage of the patterned application is that the adhesive materials, given an appropriately porous backing material, are permeable to air and water vapour and, in general, are readily redetachable.
A disadvantage of these products, however, is that if the area covered by the adhesive layer, which per se is impermeable, is too large there is a corresponding reduction in the permeability to air and water vapour, and the consumption of adhesive composition rises; and also, if the area covered by the adhesive layer is small, the adhesion properties deteriorate, i.e. the product is detached too readily from the substrate, especially in the case of heavy, textile backing materials.
Transdermal therapeutic systems (TTS) are forms of administration of medicaments which deliver one or more medicaments to the skin over a defined period at their location of use. A distinction is made here between the systemic and local administration forms. With systemic administration forms, the active substance passes through the skin into the blood stream by diffusion and can act within the body as a whole. Local administration forms can, on the other hand, act only at the sites of application. The active substance remains in the skin or in the underlying layers.
Numerous embodiments of active substance plasters have already been described in the prior art, some of which operate in accordance with the reservoir principle, where the active substance is delivered, for example, via a membrane, in some cases also with a matrix system or with a relatively complex multilayer structure.
It is also known that the adhesive composition of the plaster can be employed as the matrix comprising the active substance. In addition to self-adhesive compositions applied from solution, hotmelt self-adhesive compositions have also been proposed for this purpose, as for example in EP 0 663 431 A, EP 0 452, 034 A, EP 0 305 757 A, DE-A 43 10 012, DE-A 42 22 334 and DE-C 42 24 325. The active substances listed in these documents, if named at all, are systemic ones.
As examples of active substance plasters, mention may be made of the active substance plasters which aid the circulation, belonging to the group of locally active therapeutic systems. The use of such plasters is indicated for the treatment of rheumatic complaints, sciatica, lumbago, stiff neck, shoulder/arm pain and muscular strains and sprains, muscular aching, or muscle, joint and nerve pain in the region of the locomotor system.
Capsaicin and nonivamide are known active substances in such locally acting, circulation-aiding plasters. Because of their use on the locomotor system they are in general required to adhere strongly. Usually, the plasters are coated over their whole area with a resin-rubber adhesive composition which comprises the active substance.
However, plasters of this kind, which usually have to be applied over a relatively large area, in some cases exhibit mechanical skin irritations after removal in the case of sensitive patients. After a prolonged period of application, their removal is to some extent painful.
A further disadvantage of the known thermally active plasters with an adhesive composition based on natural rubber which is applied in the form of a solution with organic solvents to the plaster backing is the comparatively low rate of release of the active substance.
The abovementioned disadvantages, and further disadvantages, apply also to active substance plasters comprising substances other than those mentioned.
For instance, WO 94/02123 describes an active substance plaster based on pressure-sensitive hotmelt adhesive compositions and comprising low-melting and/or readily volatile active substances in a concentration of from 2.5 to 25% by weight. The polymers employed in that document are A-B-A triblock styrene-ethylene-butylene-styrene block copolymers, which are notable for low initial tack and low bond strength on skin. The component comprising active substance is not spun.
EP 0 663 431 A2, EP 0 443 759 A3, EP 0 452 034 A2 and U.S. Pat. No. 5,371,128 describe uses of pressure-sensitive, silicone-based hotmelt adhesives with various additives and in differentiated structural forms. The component comprising active substance is not spun.
DE 43 10 012 A1 describes the structure of a dermal therapeutic system comprising meltable poly(meth)acrylate mixtures. The component comprising active substance is not spun.
DE 43 16 751 C1 describes a multi-chamber system for administering active substances. The component comprising active substance is not spun.
EP 0 439 180 describes an active substance plaster for administering tulobuterol. The component comprising active substance is not spun.
EP 0 305 757 describes an active substance plaster for administering nicotine. The component comprising active substance is not spun.
EP 0 305 758 describes an active substance plaster for administering nitroglycerine. The component comprising active substance is not spun.
EP 0 305 756 describes a device for dispensing substances, and the preparation and use thereof. The component comprising active substance is not spun.
DE 37 43 945 describes a device for delivering substances, and the production process. In the case of the pressure-sensitive hotmelt adhesive composition described, which is based on SIS, the device is not self-adhesive. The processing ranges indicated therein lie well below those of hotmelt adhesive compositions and for such described systems would not provide sufficient anchorage of the adhesive composition. The component comprising active substance is not spun.
WO 96/22083 indicates a polyisobutylene adhesive for transdermal purposes, which has a tackifier with a high glass transition point. The component comprising active substance is not spun.
The object of the invention was to provide active substance plasters which, while avoiding the disadvantages known from the prior art, feature a high level of efficacy, i.e. a relatively high rate of release, and good skin compatibility coupled with good adhesion. In addition, they should be able to be prepared in a technically simple and environmentally compatible manner.
This object is achieved by active substance plasters according to the main claim. The subclaims relate to advantageous embodiments of the plasters of the invention. The invention also embraces processes for producing such plasters.
The invention accordingly provides active substance plasters consisting of a backing material and an at least partially applied adhesive composition, which are notable in that
a) a component comprising one or more active substances is additionally applied in the form of spun fibres or filaments to the backing material, this component
b) having an at least partly thermoplastic basis.
The quantitative concentrations of the active substance or substances in the component lie preferably between 0.01 and about 60% by weight, particularly preferably from 0.1 to 50% by weight.
By active substances in the context of the present invention are meant chemical elements, organic and inorganic compounds which are able to migrate from the constituents of a generic device that comprise them and so bring about a desired effect. Among the fields of use of the device of the invention, human and veterinary medicine are of particular importancexe2x80x94in this case, an embodiment of the invention in plaster form is particularly preferred.
Typical substances which can be administered by way of devices produced in accordance with the invention are:
aceclidine, amfetaminil, amfetamine, amyl nitrite, apophedrine, atebrine, alprostadil, azulene, arecoline, anethole, amylene hydrate, acetylcholine, acridine, adenosine triphosphoric acid, L-malic acid, alimemazine, allithiamine, allyl isothiocyanate, aminoethanol, apyzine, apiole, azatadine, alprenolol, ethinazone, benzoyl peroxide, benzyl alcohol, bisabolol, bisnorephedrine, butacetoluide, benactyzine, campher, colecalciferol, chloral hydrate, clemastine, chlorobutanol, capsaicin, cyclopentamine, clobutinol, chamazulene, dimethocaine, codeine, hlorpromazine, quinine, chlorothymol, cyclophosphamide, cinchocaine, hlorambucil, chlorphenesin, diethylethane, divinylethane, dexchlorpheniramine, dinoprostone, dixyrazine, ephedrine, ethosuximide, enallylpropymal, emylcamate, erythrol tetranitrate, emetine, enflurane, eucalyptol, etofenamate, ethylmorphine, fentanyl, fluanisone, guaiazulene, halothane, hyoscyamine, histamine, fencarbamide, hydroxycaine, hexylresorcinol, isoaminile citrate, isosorbide dinitrate, ibuprofen, iodine, iodoform, isoaminile, lidocaine, lopirine, levamisole, methadone, methyprylon, methylphenidate, mephenesin, methylephedrine, meclastine, methopromazine, mesuximide, nikethamide, norpseudoephedrine, menthol, methoxyfluran, methylpentinol, metixene, mesoprostol, oxy-tetracaine, oxyprenolol, oxyphenbutazone, oxyquinoline, pinene, prolintane, procyclidine, piperazine, pivazide, phensuximide, procaine, phenindamine, promethazine, pentetrazol, profenamine, perazine, phenol, pethidine, pilocarpine, prenylamine, phenoxybenzamine, Resochin, scopolamine, salicylic acid ester, sparteine, trichloroethylene, timolol, trifluoperazine, tetracaine, trimipramine, tranylcypromine, trimethadione, tybamate, thymol, thioridazine, valproic acid and verapamil, and also other active substances familiar to the skilled worker that can be absorbed through the skin, including mucosae. This list is of course not exhaustive.
Distribution of the active substances in the component takes place preferably in a thermal homogenizer, such as thermal mixers, thermal kneading apparatus, roll mills or screw systems, for example. The active substance can be added to the fully prepared component. By way of example, the active substance can also be incorporated into an intermediate stage or into the initial mixture.
The spun fibre or filament advantageously has a thickness of less than 300 xcexcm, with particular preference between 0.1 and 250 xcexcm.
In one preferred embodiment, the component is foamed and has a degree of foaming of at least 5% by volume, preferably from 10 to 75% by volume and, with particular preference between 40 and 60% by volume.
Furthermore, it has proved to be particularly advantageous for the component comprising active substance to be an adhesive composition, especially a self-adhesive composition. This adhesive composition can be identical to the adhesive composition used otherwise.
As adhesive compositions for the component comprising active substance and the components used otherwise, it is possible with advantage to employ thermoplastic hotmelt self-adhesive compositions based on natural and synthetic rubbers and on other synthetic polymers such as acrylates, methacrylates, polyurethanes, polyolefins, polyvinyl derivatives, polyesters or silicones with corresponding additives such as tackifier resins, plasticizers, stabilizers and other auxiliaries where necessary.
Their softening point should be higher than 50xc2x0 C., since the application temperature is generally at least 90xc2x0 C., preferably between 120xc2x0 C. and 150xc2x0 C. or between 180 and 220xc2x0 C. in the case of silicones. If desired, subsequent crosslinking by irradiation with UV or electron beams may be appropriate.
Hotmelt self-adhesive compositions based on block copolymers, in particular, are notable for their diverse possibilities for variation, since by the controlled reduction of the glass transition temperature of the self-adhesive composition as a consequence of the selection of the tackifiers, of the plasticizers, and of the polymer molecule size and the molecular distribution of the starting components, the required bonding to the skin that is appropriate to the function is ensured even at critical points of the human locomotor system.
The high shear strength of the hotmelt self-adhesive composition is achieved by virtue of the high cohesiveness of the polymer. The good tack comes about as a result of the pallet of tackifiers and plasticizers that is employed.
For systems with particularly strong adhesion, the hotmelt self-adhesive composition is based preferably on block copolymers, especially A-B or A-B-A block copolymers or mixtures thereof. The hard phase A is ideally polystyrene or its derivatives, and the soft phase B comprises ethylene, propylene, butylene, butadiene, isoprene or mixtures thereof; of these, particular preference is given to ethylene and butylene or mixtures thereof.
However, polystyrene blocks may also be present in the soft phase B, in amounts of up to 20% by weight. The overall styrene content should, however, always be less than 35% by weight. Preference is given to styrene contents of between 5 and 30% by weight, since a lower styrene content makes the adhesive composition more conformable.
The controlled blending of diblock and triblock copolymers is particularly advantageous, preference being given to a diblock copolymer content of less than 80% by weight.
In one advantageous embodiment the hotmelt self-adhesive composition has the following composition:
The aliphatic or aromatic oils, waxes and resins used as tackifiers are preferably hydrocarbon oils, waxes and resins, the oils, such as paraffinic hydrocarbon oils, or the waxes, such as paraffinic hydrocarbon waxes, having a favourable effect on bonding to the skin by virtue of their consistency. Plasticizers used are medium- or long-chain fatty acids and/or their esters. These additives serve to establish the adhesive properties and the stability. If desired, further stabilizers and other auxiliaries are employed.
Filling the adhesive composition with mineral fillers, fibres and hollow or solid microbeads is possible.
The hotmelt self-adhesive compositions have a softening point of in particular more than 50xc2x0 C., preferably from 70 to 220xc2x0 C. and, with particular preference, from 75 to 140xc2x0 C.
The hotmelt self-adhesive compositions are preferably formulated so that at a frequency of 0.1 rad/s they have a dynamic-complex glass transition temperature of less than 15xc2x0 C., preferably from 6 to xe2x88x9230xc2x0 C. and, with particular preference, from 3 to xe2x88x9225xc2x0 C.
Plasters in particular are subject to stringent requirements in terms of the adhesion properties. For ideal application the hotmelt self-adhesive composition should possess a high tack. There should be functionally appropriate bond strength to the skin and to the reverse of the backing. So that there is no slipping, the hotmelt self-adhesive composition is also required to have a high shear strength.
The controlled reduction of the glass transition temperature of the self-adhesive composition as a consequence of the selection of the tackifiers, of the plasticizers and of the polymer molecule size and the molecular distribution of the starting components achieves the required functionally appropriate bonding to the skin and to the reverse of the backing. The high shear strength of the self-adhesive composition employed here is achieved by virtue of the high cohesiveness of the block copolymer. The good tack comes about through the range of tackifiers and plasticizers that is employed.
Product properties such as tack, glass transition temperature and shear stability can be quantified readily using a dynamomechanical frequency measurement. In this case, use is made of a rheometer controlled by shearing stress.
The results of this measurement method give information on the physical properties of a substance by taking into account the viscoelastic component. In this context, at a defined temperature, the hotmelt self-adhesive composition is placed in oscillation between two plane-parallel plates with variable frequencies and low deformation (linear viscoelastic range). Via a pickup control unit, with computer assistance, the quotient (Q =tan xcex4) between the loss modulus (Gxe2x80x3, viscous component) and the storage modulus (Gxe2x80x2, elastic component) is determined.
Q=tan xcex4=Gxe2x80x3/Gxe2x80x2
A high frequency is chosen for the subjective sensing of the tack and a low frequency for the shear strength. A high numerical value denotes better tack and poorer shear stability.
The complex-dynamic glass transition point is the transition point from the amorphous to the viscoelastic range. It corresponds to the maximum of the temperature function at a defined frequency.
Preference is given in accordance with the invention to hotmelt self-adhesive compositions for which the ratio of the viscous component to the elastic component at a frequency of 100 rad/s at 25xc2x0 C. is greater than 0.6, or to hotmelt self-adhesive compositions for which the ratio of the viscous component to the elastic component at a frequency of 0.1 rad/s at 25xc2x0 C. is less than 0.6, preferably between 0.35 and 0.02 and, with very particular preference, between 0.3 and 0.1.
As a preferred process for the coatingxe2x80x94open-pored in accordance with the inventionxe2x80x94of air-permeable and water vapour-permeable doped adhesive layers it is possible to employ the spinning technology for applying thermoplastics and adhesives.
The contactless coating and application of hotmelt self-adhesive compositions by spinning with compressed air or inert gases is already widely employed.
With stringent requirements on uniformity and low weight per unit area, however, there are narrow limits for the coating at high viscosities. Especially when applying adhesives with a relatively high viscosity of more than 10 Pa*s, a tendency towards severe xe2x80x9cblobbingxe2x80x9d appears. On the basis of fundamental scientific research into spinning jet theory, therefore, special spinning techniques have been developed for thermoplastics of relatively high viscosity (high molecular mass).
Using the melt spin, Acufiber and Durafiber processes it is nowadays possible to process thermoplastics in the pressure-sensitive sector up to 2000 Pa*s at 200xc2x0 C. Therefore, a range of application possibilities in the sector of the spinning of thermoplastic adhesives is possible.
The advantages of this application technique, such as contactless, geometry-independent coating coupled with low thermal loading of the backings, opens up access to completely new plaster specialities.
The multiplicity of techniques are described by way of example by Acumeter, J+M Laboratories, Dynafiber and ITO Dynatex Nordson. Common to all of them are the flow processes in the spinning nozzles. Melted thermoplastics are among the group of non-newtonian liquids with pseudoplastic flow behaviour, i.e., shearing stress and coating speed are not in linear correlation with one another. The thermoplastic polymers most commonly used as hotmelt adhesives consist of linear and/or branched chain molecules. In the course of the process of aerodynamic stretching, the flow rate increases at the spun filament and the molecules become more and more disentangled and orient themselves in the flow direction.
For this reason, all nozzles utilize an internal mixing principle in which the adhesives are already surrounded by a flow of compressed air within the nozzle chamber. The narrowest gap is therefore the nozzle outlet. The outlet gap here can be circular or slot-shaped. If this spun filament is sprayed onto a substrate, the result is a random-laid nonwoven with an intrinsically linked structure. The random-laid nonwoven consists of a disordered, homogeneous arrangement of a looped continuous filament.
The doped adhesive layer, applied contactlessly via an arbitrary series of nozzles, dependent on the coating width, and spun in a weblike manner has a much higher free surface area than do full-area coatings. In contact with the skin, different release properties or release kinetics of the respective active substances and, if appropriate active-substance combinations are to be expected.
The controlled exertion of influence over, or change/increase in, the release properties is to be expected as a result of doped hotmelt pressure-sensitive adhesive coatings spun in a weblike manner, since the adhesive matrices doped over their entire area exhibit generally diffusion-controlled release characteristics.
In the text below, apparatus for producing plasters according to the invention will be explained with reference to a number of figures.